Human CD26 has been reported as a human peripheral blood T-cell surface antigen which reacts with a mouse monoclonal antibody Tal, and then established as a T-cell activation antigen because of being strongly expressed on activated T-cells (Non Patent Literatures 1 and 2). On the other hand, peptidase enzyme activity had previously been known to exist in the liver or on the cell surface of the intestinal mucosa and studied as dipeptidyl peptidase IV (DPPIV). In 1992, DPPIV and CD26 were found identical by gene cloning (Non Patent Literature 2). CD26 is composed of 766 amino acids and is a so-called type II membrane glycoprotein with its N terminus located in the cytoplasm (Non Patent Literature 3). Only 6 amino acid residues are located in the cytoplasm, while an existing signal-related motif structure is absent. Although the average molecular weight of CD26 predicted from the amino acid sequence is approximately 88 kDa, CD26 is detected as a glycoprotein of approximately 110 kDa in vivo because a region of 48 to 324 residues undergoes sugar chain modification. CD26 has the enzyme activity of a serine protease DPPIV with an active-site serine residue at position 630 and cleaves the C-terminal side of proline or alanine at position 2 counting from the N terminus of a substrate peptide.
CD26 is strongly expressed on memory T-cells in peripheral blood lymphocytes (Non Patent Literatures 4 and 5). Flow cytometry study on the expression of CD26 on resting T-cells shows 3-phase patterns as the expression intensity thereof, which can be divided into 3 populations: a population highly expressing CD26 (referred to as CD26high or CD26bright); a population moderately expressing CD26 (referred to as CD26int or CD26intermediate); and a population expressing no CD26 (referred to as CD26negative). In this context, the CD26high population is considered to play a particularly important role in immune response (Non Patent Literature 4). The CD26high population belongs to memory T-cells expressing CD45RO and reacts with a memory antigen such as tetanus toxoid, further induces the antibody production of B cells, and also has the activity of inducing MHC class I-specific killer T-cells (Non Patent Literature 4). The CD26-positive T-cells are TH1 cells, which secrete cytokines such as IL-2 or IFN-γ. These cells have migration activity between vascular endothelial cells and are considered to play an important role in local inflammation by migrating and accumulating at the inflammation site (Non Patent Literatures 3, 6, and 7).
The present inventors have found that co-stimulation with CD26 in CD8-positive T-cells also controls cytotoxic activity (Non Patent Literature 8). The present inventors have further used models with xenogeneic GVHD (graft versus host disease) developed by the transplantation of human peripheral blood mononuclear cells to NOD/Shi-scid-IL2Rγnull mice (NOG mice) and found that the activation control of T-cells by an anti-human CD26 humanized antibody is very effective for the prevention or treatment of GVHD (Non Patent Literature 9). CD26 is also expressed in various cancers, for example, lung cancer, colorectal cancer, malignant mesothelioma, kidney cancer, prostate cancer, thyroid gland cancer, gastrointestinal stromal tumor (GIST), T-cell malignant lymphoma, and glioma (Non Patent Literature 10). CD26-positive gastrointestinal stromal tumor (GIST) patients have also been reported to have a very poor prognosis (Non Patent Literature 11).
The present inventors have reported that an antibody against CD26 exerts a very effective antitumor effect on kidney cancer, malignant mesothelioma, malignant lymphoma, and the like, and developed an anti-human CD26 humanized antibody YS110, which is under phase I clinical trial targeting CD26-positive malignant mesothelioma and other CD26-positive tumors in France (anti-human CD26 humanized antibody therapy) (Patent Literature 1 and Non Patent Literatures 12 and 13).